1H-pyrazole-1-(branched)alkanamides as antiarrhythmic agents, compositions and use

ABSTRACT

N-[(alkylamino)alkyl]-3,4(or 4,5)-diaryl-1H-pyrazole-1-(branched)alkanamides and pyrazole-1-alkanamines useful for treating cardiac arrhythmias in mammals, are prepared by reacting a lower-alkyl ester of pyrazole-1-acetic acid with an appropriate diamine followed by reduction or by reacting the anion of a lower-alkyl ester of a pyrazole-1-acetic acid with an alkylating agent followed by displacement of the ester by an appropriate amine.

This application is a division, of application Ser. No. 327,228, filedMar. 22, 1989 now U.S. Pat. No. 4,916,150.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel N-[(alkylamino)alkyl]-3,4(or4,5)-diaryl 1H-pyrazole-1-(branched)alkanamides andpyrazole-1-alkanamines, process for the synthesis of saidpyrazole-1-alkanamides, and alkanamines and methods for treating cardiacarrhythmia in mammals utilizing said pyrazole-1-alkanamides andalkanamines.

INFORMATION DISCLOSURE STATEMENT

U.S. Pat. No. 4,695,566 to Heinemann et. al., discloses as antiarrythmicagents 1H-pyrazol-3-yl(and 1H-pyrazol-5-yl)oxyacetamides of generalformula ##STR1##

Specifically disclosed are (1)N-[2-(diethylamino)ethyl]-2-[(5-phenyl-1H-pyrazol-3-yl)oxy]acetamide,example 5, and (2)N-[3-(diethylamino)propyl]-2-[(5-phenyl-1H-pyrazol-3-yl)oxy]acetamide,example 24.

U.S. Pat. No. 4,182,895, to Bailey and the related article by Bailey etal. [J. Med. Chem. 28, 256-260(1985)] disclose six1-amino-lower-alkyl-3,4-diphenyl pyrazoles, two of which haveantidepressant activity, and three of which have analgesic activity.Also disclosed as an intermediate is"β-[1-(3,4-diphenyl-1H-pyrazolyl)]-N,N-dimethylpropionamide".

Ezrin et al. [FASEB Journal 2, A1557(1988)] describe the antiarrhythmicactivity ofN-[3-(diethylamino)propyl]-4,5-diphenyl-1H-pyrazole-1-acetamidefumarate.

European patent application No. 299,407, published Jan. 18, 1989discloses a series of 4,5-diaryl-1H-pyrazole-1-alkanamides asantiarrhythmic agents.

Bondavalli et al. [Farmaco, Ed. Sci 43, 725-743(1988)] disclose N-alkylcarbamates of 1-(2-hydroxyethyl)-3,5-diphenyl-1H-pyrazole asantihypertensive, antiarrhythmic, analgesic, antiinflammatory andhypoglycemic agents. Specifically disclosed are the ethyl, isopropyl,phenyl and 1-naphthyl carbamates.

U.S. Pat. No. 4,072,498 to Moon and Kornis discloses a series ofpyrazole-1-acetamide herbicides includingN,N,α,α-tetramethyl-3,4-diphenylpyrazole-1-acetamide (example 160),3-(2-methylphenyl) and3-(2-chlorophenyl)-N,N,α,α,tetramethyl-1H-pyrazole-1-acetamide (example65 and 66) and 3-phenyl-N,N,α-triethyl-1H-pyrazole-1-acetamide (example86).

SUMMARY OF THE INVENTION

In a product aspect the invention relates to compounds of the formula I##STR2## or acid addition salt or solvate thereof wherein R¹ is hydrogenor lower-alkyl; R² and R³ are independently hydrogen, hydroxy,lower-alkyl, lower-alkoxy, or halo; R⁴ and R⁵ are independently hydrogenor lower-alkyl, or R⁴ and R⁵ together form a straight or branchedalkylene chain of four to six carbon atoms; R⁶ and R⁷ are independentlyhydrogen or straight-chain lower-alkyl; r is zero or one; q is one whenr is zero; q is zero when r is one and in that case at least one of R⁶and R⁷ is not hydrogen; and A is CH₂ CH(OH)CH₂ or (CH₂)_(n) wherein n isan integer from two to eight.

Lower-alkyl as used herein describes linear or branched hydrocarbonchains of four or fewer carbon atoms; lower-alkoxy as used hereindescribes linear or branched alkyloxy substituents containing four orfewer carbon atoms; halogen describes bromine, chlorine or fluorine.

In a further product aspect, the invention relates to compositions fortreating cardiac arrhythmia which comprise compounds of the formula Itogether with pharmaceutically acceptable excipients or diluents asrequired.

In a process aspect, the invention relates to a method for treatingcardiac arrhythmia in a mammal which comprises administering to saidmammal an antiarrhythmically effective amount of a compound of formulaI.

Processes for preparing a compound of formula I in which r is zerocomprise reacting a pyrazole-1-acetate with an amine followed byreduction of the amide carbonyl. Further processes for preparing acompound of formula I in which q is zero and at least one of R⁶ and R⁷is lower-alkyl, comprise reacting the anion of a 3,4 or4,5-disubstituted pyrazole-1-acetate with an alkylating agent followedby reaction of the ester with an amine.

DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS

The synthesis of compounds of the invention may be outlined as shown inscheme A wherein R⁸ is lower-alkyl. ##STR3##

A lower-alkyl ester, preferably a methyl or ethyl ester of a suitablysubstituted 3,4 or 4,5-diphenyl-1H-pyrazole-1-acetic acid (II) in asuitable solvent, preferably THF, is treated with a base of sufficientstrength to form the carbanion at the α-carbon, preferably lithiumdiisopropylamide, at -78° to 20° C., preferably at -78° C. A compoundconsisting of the alkyl group R⁷ attached to a group X that is subjectto nucleophilic displacement (X=Cl, Br, I, or sulfonate) preferably thealkyl iodide, is added and the α-alkylated product, III, is formed. If asecond α-alkyl group is desired (i.e. R⁶ and R⁷ both lower-alkyl) theprocess may be repeated.

Alternatively the compound II where R⁶ is lower-alkyl or compound IIIwhere R⁷ is hydrogen may be synthesized from a known3,4-diphenyl-1H-pyrazole by alkylation with an α-haloalkanoate when theα-alkyl 3,4-diphenyl-1H-pyrazole-1-acetate is desired. A solution of theappropriate diphenylpyrazole and an excess, preferably about a 3-foldexcess, of the appropriate α-haloalkanoate, preferably theα-bromoalkanoate, in a suitable solvent is teated with an excess,preferably a 10 to 50% excess, of a suitable base, preferably sodiumhydride, at -20° to 100° C., preferably about 25° C. Minor amounts ofthe 4,5-diphenylpyrazole-1-alkanoates are also formed in the reaction,due apparently to steric effects of R⁶, and are usually removed bysubsequent crystallization or chromatography.

The lower-alkyl ester, III, is reacted with an excess of a primary orsecondary amine of formula IV at 20° to 150° C., preferably at 90° to150° C. When the amine is valuable, the ester III is preferably reactedwith about one equivalent of the amine IV in the presence of a tertiaryamine, preferably diisopropylethylamine, optionally in an inert solvent.

When products wherein r is zero (Ib) are desired, the appropriatepyrazole-1-alkanamide (Ia) in an inert solvent is reacted with anexcess, preferably an 8 to 10-fold molar excess, of a reducing agentsuch as lithium aluminum hydride or, preferably, diborane at -20° C. to100° C., preferably at about 65° C.

The compounds of the invention wherein A is (CH₂)_(n) may also besynthesized as outlined in scheme B. ##STR4##

A lower-alkyl ester, preferably a methyl or ethyl ester of a suitablysubstituted 3,4- or 4,5-diphenyl-1H-pyrazole-1-alkanoic acid III isreacted with an excess of a primary or secondary -aminoalkanol Voptionally in the presence of a base/solvent such as pyridine at -20° to20° C., preferably at 90°-100° C. to produce anN-[-hydroxyalkyl]pyrazole-1-alkanamide of formula VI. Thehydroxyalkylalkanamide VI is activated preferably by sulfonylation,preferably with methanesulfonyl chloride, in the presence of abase/solvent such as pyridine at -20° to 20° C., preferably at 0° C., toproduce an alkylalkanamide of formula VII wherein Y is a group which issubject to nucleophilic displacement such as toluenesulfonate ormethanesulfonate.

Alternatively, the hydroxyalkylalkanamide VI is converted to thecorresponding halide VII, (Y=Cl, Br or I) by phosphorus trihalide,phosphorus pentahalide, thionyl halide or tetrahalomethane withtrialkylphosphine. The group Y is then displaced by reaction in thepresence or absence of solvent with an appropriate primary or secondaryamine VIII at 20° to 100° C.

The ester III may be synthesized from the appropriately substituteddesoxybenzoin by formylation by means of known procedures [Russel et alJ. Am. Chem. Soc. 76, 5714(1954)] followed by condensation with ahydrazinoacetic acid ester in a suitable solvent, preferably ethanol, at20° to 100° C., preferably at 25° C. The hydrazinoacetate is preferablyused in the form of a mineral acid salt from which the free hydrazine isliberated in situ by the addition of about one equivalent of a base,preferably pyridine.

When only the 4,5-diphenyl isomer of the products of formula I isdesired, the 4,5-diphenyl ester III may be synthesized from theappropriately substituted desoxybenzoin by a two-step procedurecomprising reaction with N,N-dimethylformamide dimethyl acetal in aninert solvent, preferably methyl tert-butyl ether, at 20°-100° C.preferably at about 55° C., followed by cyclization with a lower-alkylester of hydrazinoacetic acid as described above.

The compounds of formulas Ia and Ib are useful both in the free baseform and the form of acid-addition salts, and both forms are within thepurview of the invention. The acid-addition salts are in some cases amore convenient form for use, and in practice the use of the salt forminherently amounts to the use of the base form. The acids which can beused to prepare the acid-addition salts include preferably those whichproduce, when combined with the free base, medicinally acceptable saltsthat is, salts whose anions are relatively innocuous to the animalorganism in medicinal doses of the salts so that the beneficialproperties inherent in the free base are not vitiated by side effectsascribable to the anions. In practicing the present invention it isconvenient to form the hydrochloride, fumarate, toluenesulfonate,methanesulfonate, or maleate salts. However, other appropriatemedicinally acceptable salts within the scope of the invention are thosederived from other mineral acids and organic acids. The acid-additionsalts of the basic compounds are prepared either by dissolving the freebase in aqueous alcohol solution containing the appropriate acid andisolating the salt by evaporating the solution, or by reacting the freebase and an acid in an organic solvent, in which case the salt separatesdirectly, is precipitated with a second organic solvent, or can beobtained by concentration of the solution. Although medicinallyacceptable salts of the basic compounds are preferred, all acid-additionsalts are within the scope of the present invention. All acid-additionsalts are useful as sources of the free base form even if the particularsalt per se is desired only as an intermediate product, as, for example,when the salt is formed only for purposes of purification oridentification, or when it is used as an intermediate in preparing amedicinally acceptable salt by ion exchange procedures.

The structures of the compounds of the invention were established by themode of synthesis, by elemental analysis, and by infrared, ultravioletand nuclear magnetic resonance spectroscopy. The course of the reactionsand the identity and homogeneity of the products were assessed by thinlayer chromatography (TLC) or gas-liquid chromatography (GLC). Thestarting materials are either commercially available or may be preparedby procedures well known in the art.

In the following procedures melting points are given in degrees C andare uncorrected. The abbreviation THF stands for tetrahydrofuran, DMFstands for N,N-dimethylformamide and Ac stands for acetyl residue, CH₃CO.

EXAMPLE 1A Ethyl 4,5-diphenyl-1H-pyrazole-1-acetate

A slurry of 200 g (0.89 mol) of formyldesoxybenzoin and 138 g (0.89 mol)of ethyl hydrazinoacetate hydrochloride in 2 L of ethanol were stirredat room temperature and 72 mL (0.89 mol) of pyridine was added dropwise.The reaction was stirred at room temperature and progress was assessedby periodic TLC using 3% acetic acid, 25% acetone and 72% toluene onsilica gel. When, after the addition of a further 3 mL of pyridine overthe course of 18 hours, the reaction was judged complete by TLC, thesolvent was stripped in vacuo and the residue slurried in ethyl acetate.The ethyl acetate solution was filtered free of solid impurity, washedwith water then saturated sodium chloride solution and dried overmagnesium sulfate. The ethyl acetate was stripped to a reddish oil whichwas triturated in pentane to yield 156 g of solid. The product wasrecrystallized carefully from ether-pentane to yield 44.6 g of ethyl4,5-diphenyl-1H-pyrazole-1-acetate, mp 79°-81° C. By repeated carefulcrystallization from ether-pentane a further 99.6 g of the 4,5-diphenylisomer may be obtained for a total yield of 144.2 g (53% yield).

EXAMPLE 1B Ethyl 4,5-Diphenyl-1H-pyrazole-1-acetate

When only the 4,5-diphenyl isomer is desired the following procedure ispreferred. A mixture of 778 g (3.96 mol) deoxybenzoin, 580 mL (4.38 mol)of N,N-dimethylformamide dimethyl acetal, and 775 mL of methyltert-butyl ether was refluxed for 3 hours. The reaction mixture wascooled on ice to 0°-5° C. The precipitated solid was collected byfiltration, the filter cake washed with 250 mL of cold methyl tert-butylether twice and dried in vacuum chamber at 65° C. to afford 913 g (92%)of 3-(dimethylamino)-1,2-diphenyl-2-propen-1-one, mp 128°-133° C. Aslurry of 913 g (3.64 mol) of3-(dimethylamino)-1,2-diphenyl-2-propen-1-one in 3.4 L of absoluteethanol was treated with 618 g (4 mol) of ethyl hydrazinoacetatehydrochloride in one portion. The mixture was stirred at roomtemperature for 1 hour, filtered through diatomaceous earth, and thefiltrate treated with 7 L of 50% aqueous ethanol with stirring. Coolingof the resultant solution to 0°-5° C. provided a white solid which wascollected by filtration, washed with 250 mL of cold 50% ethanol twiceand dried in vacuum at 40° C. to provide 970 g (87%) of ethyl4,5-diphenyl-1H-pyrazole-1-acetate, mp 76°-80° C., containing none ofthe 3,4-diphenyl isomer detectable by GLC.

EXAMPLE 2 Ethyl 3,4-diphenyl-1H-pyrazole-1-acetate

Chromatography of the mother liquors from Example 1A on silica gel using1:1 chloroform-hexane provided up to 20% of the 3,4-diphenyl isomer. The3,4-diphenyl isomer (Example 2) may be distinguished from the4,5-diphenyl isomer (Example 1) by its higher Rf on TLC. An analyticalsample may be obtained by distillation at 0.2 mm, boiling range186°-189° C.

EXAMPLE 3 Ethyl 4,5-bis(4-fluorophenyl)-1H-pyrazole-1-acetate and ethyl3,4-bis(4-fluorophenyl)-1H-pyrazole-1-acetate

Following the procedure of Example 1, 19.7 g (0.076 mol) of1,2-bis(4-fluorophenyl)-3-hydroxy-2-propen-1-one, 11.8 g (0.076 mol) ofethyl hydrazinoacetate hydrochloride and 6.3 mL (0.078 mol) of pyridinewere reacted at room temperature to produce 19.9 g of the mixed 4,5- and3,4-diphenyl isomers. The isomers were separated by high pressure liquidchromatography on silica gel eluting with 97% toluene, 3% ethyl acetate.The peak with k'=2.0 yielded 1.8 g of the 3,4-diphenyl isomer, mp98°-99° C., and the peak with k'=4.0 yielded 11.16 g of the 4,5-diphenylisomer, mp 83°-84° C.

EXAMPLE 4 Ethyl 4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-acetate

Following the procedure of example 1B 11 g (0.39 mol) of3-(dimethylamino)-2-(4-methoxyphenyl)-1-phenyl-2-propene-1-one and 6.6 g(0.43 mol) of ethyl hydrazinoacetate hydrochloride were reacted in 55 mLof absolute methanol under nitrogen. After 11/2 hours, 11.2 g of solidproduct was filtered off, mp 81°-84° C.

EXAMPLE 5 Ethyl 5-(4-hydroxyphenyl)-4-phenyl-1H-pyrazole-1-acetate

Following the procedure of example 1B, 15 g (0.05 mol) of3-(dimethylamino)-1-(4-hydroxyphenyl)-2-phenyl-2-propene-1-one and 9 g(0.058 mol) of ethyl hydrazino acetate hydrochloride were reacted in 75mL of absolute ethanol. After 11/2 hours, 14.38 g of solid product wasfiltered off, mp 130°-135° C.

EXAMPLE 6 Ethyl 4-(4,fluorophenyl)-5-phenyl-1H-pyrazole-1-acetate

Following the procedure of example 1B, 13.8 g (0.0645 mol) of2-(4-fluorophenyl)-1-phenylethanone was reacted with 20 mL of dimethylformamide dimethyl acetal to yield 13.6 g of3-(dimethylamino)-2-(4-fluorophenyl)-1-phenyl-2-propen-1-one, mp115°-116° from isopropyl acetate. The enamine (10.5 g, 0.039 mol) wasreacted with 6.03 g (0.039 mol) of ethyl hydrazinoacetate hydrochlorideto yield 12.1 g of product mp 86°-87° C. from methyl-t-butyl ether.

EXAMPLE 7 Ethyl 4-(4-chlorophenyl)-5-phenyl-1H-pyrazole-1-acetate

By a procedure analogous to that of example 6, 8.5 g of ethyl4-(4-chlorophenyl)-5-phenyl-1H-pyrazole-1-acetate mp 75°-76° fromtriethylamine, was synthesized from 11.48 g (0.049 mol) of2-(4-chlorophenyl)-1-phenylethanone, 12 mL of dimethylformamide dimethylacetal and 4.95 g (0.032 mol) of ethyl hydrazinoacetate hydrochloride.

EXAMPLE 8 Ethyl 4,5-diphenyl-α-methyl-1H-pyrazole-1-acetate

A solution of lithium diisopropylamide was prepared by adding at -15° C.under nitrogen (0.108 mol) of diisopropyl amine to 43.5 mL (0.108 mol)of 2.5M n-butyllithium in hexane that had been diluted with 200 mL THF.A solution of 30 g (0.098 mol) of ethyl4,5-diphenyl-1H-pyrazole-1-acetate of example 1 in 300 mL of THF wascooled to -78° C. and the solution of diisopropylamide was added undernitrogen. The reaction was stirred 1 hr at -78° C., 30 mL (0.049 mol) ofmethyl iodide was added, and the stirring was continued 30 minutes at-78° C. before allowing the reaction to come to room temperature. Thereaction was quenched with 30 mL of saturated aqueous ammonium chlorideand the solvent was stripped. The residue was dissolved in ethylacetate, washed with water, dried, stripped and put through a silica gelcolumn with a gradient of 5% to 50% ethyl acetate in hexane. The productwas obtained as 27 g of an oil which could be crystallized, if desired,from ethyl acetate-hexane.

EXAMPLE 9 Ethyl 3,4-Diphenyl-α-methyl-1H-pyrazole-1-acetate

A. A solution of 45.2 g (0.205 mol) of 3,4-(4,5)-diphenylpyrazole and 80mL (0.616 mol) of ethyl 2-bromopropionate in DMF at room temperature wastreated with 13.8 g (0.37 mol) of a 60% dispersion of sodium hydride inmineral oil. The mixture was stirred 3 days, poured into water,extracted into ethyl acetate, stripped, and put through a silica gelcolumn using a gradient from 2% to 5% ethyl acetate in hexane. Afterstripping solvent, the fractions containing the slower-running of thetwo major components yielded 27.8 g of ethyl3,4-diphenyl-α-methyl-1H-pyrazole-1-acetate as an oil containing about11% of the 4,5-isomer.

B. By a procedure substantially similar to that of example 8, it iscontemplated that ethyl 3,4-diphenyl-α-methyl-1H-pyrazole-1-acetate maybe synthesized from ethyl 3,4-diphenyl-1H-pyrazole-1-acetate of example2 and methyl iodide.

EXAMPLE 10 Ethyl α,α-dimethyl-4,5-diphenyl-1H-pyrazole-1-acetate

By a procedure substantially similar to that of example 8, it iscontemplated that ethyl α,α-dimethyl-4,5-diphenyl-1H-pyrazole-1-acetatemay be synthesized from ethyl4,5-diphenyl-α-methyl-1H-pyrazole-1-acetate of example 8 and methyliodide.

EXAMPLE 11Ethyl-α-ethyl-4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-acetate

By a procedure substantially similar to that of example 8, it iscontemplated thatethyl-α-ethyl-4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-acetate may besynthesized from ethyl4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-acetate of example 4 andethyl iodide.

EXAMPLE 12N-[3-(diethylamino)propyl]-4,5-diphenyl-1H-pyrazole-1-acetamidehemihydrate

A. A mixture of 8 g (0.026 mol) of ethyl4,5-diphenyl-1H-pyrazole-1-acetate of example 1 and 40 mL (0.25 mol) ofdiethylaminopropylamine was heated on a steam bath under nitrogen for 14hours. The excess diethylaminopropylamine was stripped in vacuo and theresidue dissolved in ether. The ether solution was washed two times withwater, once with saturated sodium chloride, dried over magnesiumsulfate, filtered and evaporated in vacuo. The resulting white residuewas dissolved in ether and a small amount of undesired material wasremoved by filtration after addition of some pentane. The filtrate wasstripped, redissolved in ether, dried over magnesium sulfate, treatedwith decolorizing carbon, filtered and evaporated. The resulting residuewas triturated in water filtered and rinsed with water to yield 8.55 g(82%) of N-[3-(diethylamino)propyl]-4,5-diphenyl-1H-pyrazole-1-acetamidehemihydrate, mp 70°-74° C. The product can be recrystallized from wetether.

B. The methane sulfonate salt was prepared by dissolving 6 g of the freebase in 150 mL of isopropyl alcohol and treating with one equivalent ofmethanesulfonic acid; mp 166°-168° C.

C. The fumarate salt was prepared by dissolving 70 g of the free base in250 mL of hot isopropyl alcohol, adding 20.8 g of fumaric acid in 100 mLof methanol, refluxing, filtering, and cooling. There was obtained 83 gof N-[3-(diethylamino)propyl]-4,5-diphenyl-1H-pyrazole-1-acetamide(E)-2-butenedioate (1:1), mp 154°-156° C.

For large scale preparation ofN-[3-(diethylamino)propyl]-4,5-diphenyl-1H-pyrazole-1-acetamide(E)-2-butenedioate (1:1) the following procedure was found to besuperior: A solution of 2.2 kg (7.3 mol) of ethyl4,5-diphenyl-1H-pyrazole-1-acetate in 4.3 kg (33 mol) of3-diethylaminopropylamine was heated at 135°-148° C. for 1.5 hours whiledistilling off ethanol. Excess amine was removed by vacuum distillation;the residue was dissolved in 6 L of isopropyl acetate and washed twicewith 3 L of water. The organic layer was concentrated to a white solid,which was dissolved in 14 L of ethanol, treated with 0.96 kg (8.3 mol)of fumaric acid, and heated to 75° C. to achieve a clear solution. Thesolid product was obtained by filtration of the cooled solution. Thefirst crop weighed 3.1 kg (84% yield) and melted at 157°-159° C.; asecond crop, m.p. 155°-157° C., 0.36 kg (9%) was obtained uponconcentration of the mother liquors.

D. The toluenesulfonate salt was prepared by dissolving 70 g of the freebase in 250 mL of hot isopropyl alcohol, treating with 34 g ofp-toluenesulphonic acid monohydrate in 100 mL of isopropyl alcohol,filtering and cooling. There was obtained 96.8 g of the toluenesulfonatesalt, mp 126°-129° C.

E. The maleate salt was prepared by dissolving 70 g the free base in 250mL of isopropyl alcohol and 1 L of isopropyl acetate, adding 20.8 g ofmaleic acid, refluxing, cooling and stripping. The resulting residue wassuspended in about 600 mL of ethyl acetate and 12.8 mL of water wasadded with vigorous stirring. The resulting solid was filtered off andrecrystallized from 300 mL of water to yield 58.9 g ofN-[3-(diethylamino)propyl]-4,5-diphenyl-1H-pyrazole-1-acetamide(Z)-2-butenedioate (1:1) sesquihydrate, mp 70°-71° C.

EXAMPLE 13N-[3-(Dimethylamino)propyl]-4,5-diphenyl-1H-pyrazole-1-acetamidemonohydrochloride hemihydrate

A mixture of 86.5 g (0.28 mol) of ethyl4,5-diphenyl-1H-pyrazole-1-acetate of Example 1 and 340 mL (2.8 mol) ofdimethylaminopropylamine was stirred on a steam bath under nitrogen for18 hours. The excess dimethylaminopropylamine was stripped in vacuo, theresidue was dissolved in 700 mL of ether and washed two times withwater. On washing with saturated sodium chloride solution, the etherlayer solidified. The resulting solid was filtered off and dissolved indichloromethane, washed with saturated sodium chloride solution, andstripped. The residue was slurried in water and the solid productfiltered off. After thorough drying, it was dissolved in 700 mL ofabsolute ethanol, treated with a slight excess of ethanolic HCl,filtered free of some undesired solids, and stripped. The residue wasrecrystallized from about 800 mL of ethanol by chilling to yield 79 g ofthe hydrochloride ethanol solvate, mp 101°-104° C., which showed asingle spot on TLC on silica gel with 5% isopropyl amine in chloroformas eluant. The ethanol solvate was dissolved in about 800 mL of warmisopropyl alcohol and stripped; the process was repeated and theresulting residue was crystallized from about 350 mL of wet THF byrecycling the mother liquor several times to yield 26.2 g ofN-[3-(dimethylamino)propyl]-4,5-diphenyl-1H-pyrazole-1-acetamidemonohydrochloride hemihydrate, mp 118°-121° C.

EXAMPLE 14N-[2-(Dimethylamino)ethyl]-4,5-diphenyl-1H-pyrazole-1-acetamidehemihydrate

A mixture of 9 g (0.029 mol) of ethyl 4,5-diphenyl-1H-pyrazole-1-acetateof Example 1 and 31 mL (0.029 mol) of dimethylaminoethylamine wasstirred on a steam bath under nitrogen for 18 hours. The excessdimethylamino ethylamine was stripped in vacuo, the residue dissolved in300 mL of ether, treated with decolorizing carbon, filtered, andstripped to approximately 10 g of residue. This was triturated in water,filtered, washed and recrystallized from ether to yield 7.16 g ofN-[2-(dimethylamino)ethyl]-4,5-diphenyl-1H-pyrazole-1-acetamidehemihydrate, mp 85°-88° C.

EXAMPLE 15N-[6-(Dimethylamino)hexyl]-4,5-diphenyl-1H-pyrazole-1-acetamide

A mixture of 8 g (0.026 mol) of ethyl 4,5-diphenyl-1H-pyrazole-1-acetateof Example 1, 4.1 g (0.028 mol) of dimethylaminohexylamine and 33.3 mL(0.19 mol) of diisopropylethylamine was stirred on a steam bath undernitrogen for 18 hours. Thin layer chromatography on silica gel with 5%isopropylamine in chloroform showed incomplete reaction. Another 1 mL ofdimethylaminohexylamine was added and stirring continued on a steam bathfor an additional 24 hours. The reaction was stripped in vacuo, taken upin 200 mL of ether, washed two times with water, washed once with halfsaturated sodium bicarbonate solution, washed with water again, washedwith saturated sodium chloride solution, dried over magnesium sulfate,treated with decolorizing carbon, filtered and stripped. The residue wastaken up in ether and treated with a slight excess of hydrochloric acid.The hydrochloride salt was extracted into water and washed three timeswith ether; the water layer was chilled, and made basic with solidsodium carbonate and extracted two times with ether. The ether extractswere combined, washed once with saturated sodium chloride, dried overmagnesium sulfate, treated with decolorizing carbon, filtered andstripped. The resulting residue was triturated in pentane to yield 4.14g of N-([6-(dimethylamino)hexyl]-4,5-diphenyl-1H-pyrazole-1-acetamide,mp 60°-63° C.

EXAMPLE 16N-[4-(Dimethylamino)butyl]-4,5-diphenyl-1H-pyrazole-1-acetamide

By a procedure substantially similar to that of Example 15, 3.91 g ofN-[4-(dimethylamino)butyl]-4,5-diphenyl-1H-pyrazole-1-acetamide, mp77°-79° C., was synthesized from 8 g (0.026 mol) of ethyl4,5-diphenyl-1H-pyrazole-1-acetate, 3.4 g of dimethylaminobutylamine(0.029 mol) and 33.3 mL (0.18 mol) of diisopropylethylamine.

EXAMPLE 17N-[2-(Diethylamino)ethyl1-4,5-diphenyl-1H-pyrazole-1-acetamide

By a procedure involving reaction conditions substantially similar tothose of Example 14 and a workup substantially similar to that ofExample 12, 6.46 g ofN-[2-(diethylamino)ethyl]-4,5-diphenyl-1H-pyrazole-1-acetamide, mp67°-69° C., was synthesized from 10 g of ethyl4,5-diphenyl-1H-pyrazole-1-acetate and 46.4 mL ofN,N-diethylethylenediamine. The product was recrystallized from ether.

EXAMPLE 184,5-Diphenyl-N-[2-(1-piperidinyl)ethyl]-1H-pyrazole-1-acetamide

By a procedure substantially similar to that of Example 15, 10.57 g of4,5-diphenyl-N-[2-(1-piperidinyl)-ethyl]-1H-pyrazole-1-acetamide wassynthesized from 15 g of ethyl 4,5-diphenyl-1H-pyrazole-1-acetate, 9.2 gof N-(2-aminoethyl)piperidine, and 62 mL of diisopropylethylamine. Thework up did not require extraction, as the product crystallized from thecooled reaction mixture. It was recrystallized very slowly from 250 mLof 1:3 THF-ether, mp 95°-97° C.

EXAMPLE 194,5-Diphenyl-N-[3-(1-pyrrolidinyl)propyl]-1H-pyrazole-1-acetamide

By a procedure substantially similar to that of Example 14, 5.52 g of4,5-diphenyl-N-[3-(1-pyrrolidinyl)propyl1-1H-pyrazole-1-acetamide, mp75°-79° C., was prepared from 15 g of ethyl4,5-diphenyl-1H-pyrazole-1-acetate and 60 mL ofN-(3-aminopropyl)pyrrolidine.

EXAMPLE 204,5-Diphenyl-N-[2-(1-pyrrolidinyl)ethyl]-1H-pyrazole-1-acetamide

By a procedure substantially similar to that of Example 18, 6.67 g of4,5-diphenyl-N-2-(1-pyrrolidinyl)ethyl-]1H-pyrazole-1-acetamide, mp80°-84° C., was prepared from 15 g (0.049 mol) of ethyl4,5-diphenyl-1H-pyrazole-1-acetate of Example 1, 9 mL (0.072 mol) ofN-(2-aminoethyl)pyrrolidine and 62 mL (0.36 mol) ofdiisopropylethylamine.

EXAMPLE 214,5-Diphenyl-N-[3-(1-piperidinyl)propyl]-1H-pyrazole-1-acetamidehemihydrate

A mixture of 15 g (0.049 mol) of ethyl4,5-diphenyl-1H-pyrazole-1-acetate of Example 1, 10.2 g (0.02 mol) of3-aminopropylpiperidine, and 62 mL of diisopropylethylamine was stirredon a steam bath under nitrogen for 18 hours. The excess amine wasstripped in vacuo. The residue was taken up in about 300 mL of ether andwashed twice with water. The product was extracted into 150 mL of coldwater containing 18 mL of 10% hydrochloric acid. The water layer waswashed two times with ether, treated with decolorizing carbon, filtered,chilled and made basic with solid sodium carbonate. The product wasextracted into methylene dichloride, dried over sodium sulfate,filtered, and stripped to 14.7 g of solid residue. The residue wastriturated in water, filtered and dried to yield 12.36 g of4,5-diphenyl-N-[3-(1-piperdinyl)propyl]-1H-pyrazole-1-acetamidehemihydrate, mp 81°-85° C.

EXAMPLE 22 N-[3-(Diethylamino)propyl]-4,5-bis(4-fluorophenyl)-1H-pyrazole-1-acetamide

By a procedure substantially similar to that of Example 14, 8 g (0.023mol) of ethyl 4,5-bis(4-fluorophenyl)-1H-pyrazole-1-acetate of Example 3and 34.3 mL (0.22 mol) of diethylaminopropylamine were reacted toproduce 4.45 g ofN-[3-(diethylamino)propyl]-4,5-bis(4-fluorophenyl)-1H-pyrazole-1-acetamide.The solid product after trituration in water collapsed to anon-crystalline, white, waxy solid upon drying.

EXAMPLE 23N-[3-(Diethylamino)propyl]-N-methyl-4,5-diphenyl-1H-pyrazole-1-acetamide(E)-2-butenedioate (1:1)

A mixture of 28.7 g (0.09 mol) of ethyl4,5-diphenyl-1H-pyrazole-1-acetate of Example 1, 19.7 g (0.13 mol) ofdiethylaminopropylmethylamine, and 94 mL (0.54 mol) ofdiisopropylethylamine was refluxed under nitrogen for seven days. Thereaction was stripped and applied to a silica gel column usingdichloromethane. Impurities were eluted with dichloromethane followed by1.25% isopropylamine in dichloromethane. The product was eluated with1.25% isopropylamine in chloroform. The 8 g of product was dissolved in40 mL of warm acetone and treated with 2.3 g of fumaric acid. Uponcooling, there was obtained 9.87 g ofN-[3-(diethylamino)propyl]-N-methyl-4,5-diphenyl-1H-pyrazole-1-acetamide(E)-2-butenedioate(1:1), mp 139°-141° C.

EXAMPLE 24N-[3-[bis(1-methylethyl)amino]propyl]-4,5-diphenyl-1H-pyrazole-1-acetamide

By a procedure substantially similar to that of Example 15, 2.49 g ofN-[3-[bis(1-methylethyl)amino]propyl]-4,5-diphenyl-1H-pyrazole-1-acetamide,mp 83°-84° C., was synthesized from 12 g (0.039 mol) of ethyl4,5-diphenyl-1H-pyrazole-1-acetate, 6.2 g (0.039 mol) ofdiisopropylaminopropylamine, and 35 mL of diisopropylethylamine.

EXAMPLE 25N-[3-(Diethylamino)-2-hydroxypropyl]-4,5-diphenyl-1H-pyrazole-1-acetamide

By a procedure substantially similar to that of Example 15, 8.9 g ofN-[3-(diethylamino)-2-hydroxypropyl]-4,5-diphenyl-1H-pyrazole-1-acetamide,mp 70°-72° C., was synthesized from 15 g (0.049 mol) of ethyl4,5-diphenyl-1H-pyrazole-1-acetate, 10 g (0.69 mol) of1-amino-3-diethylamino-2-propanol, and 57 mL of diisopropylethylamine.

EXAMPLE 26N-[3-(Dimethylamino)propyl]-3,4-diphenyl-1H-pyrazole-1-acetamide(E)-2-butenedioate (1:1)

A mixture of 8.35 g (0.027 mol) of ethyl3,4-diphenyl-1H-pyrazole-1-acetate of Example 2 and 33.4 mL (0.26 mol)of dimethylaminopropylamine was stirred on a steam bath under nitrogenfor 18 hours. The reaction was stripped to dryness, the residuedissolved in dichloromethane, washed twice with water and once withsaturated sodium chloride solution. The product was extracted into about100 mL of cold water containing about 12 mL of 10% HCl. The water layerwas made basic with solid sodium carbonate and the product extractedinto methylene dichloride, dried over sodium sulfate and stripped. Theproduct was purified by chromatography on silica gel eluting with 5%triethylamine in chloroform. The purified product was crystallized fromacetone as the fumurate salt and was recrystallized from ethanol toyield 4 47 g ofN-[3-(dimethylamino)propyl]-3,4-diphenyl-1H-pyrazole-1-acetamide(E)-2-butenedioate (1:1), mp 163°-168° C.

EXAMPLE 27N-[3-(Diethylamino)propyl]-3,4-diphenyl-1H-pyrazole-1-acetamide

By a procedure substantially similar to that of Example 26, omitting theformation of the fumarate salt, 9 g ofN-[3(diethylamino)propyl]-3,4-diphenyl-1H-pyrazole-1-acetamide wasprepared from 10 g (0.033 mol) of ethyl3,4-diphenyl-1H-pyrazole-1-acetate and 50 mL (0.32 mol) ofdiethylaminopropylamine. The product was an oil.

EXAMPLE 283,4-Diphenyl-N-[2-(1-piperidinyl)ethyl-]1H-pyrazole-1-acetamide

By a procedure substantially similar to that of Example 18, 14.0 g of3,4-diphenyl-N-[2-(1-piperidinyl)ethyl]1H-pyrazole-1-acetamide wasprepared from 16.4 g (0.054 mol) of ethyl3,4-diphenyl-1H-pyrazole-1-acetate, 10 g (0.07 mol) of2-aminoethylpiperidine, and 65 mL (0.37 mol) of diisopropylethylamine.The product was not recrystallized but was triturated in ether, mp120°-124° C. A second polymorph of mp 142°-144° C. may be obtained byrecrystallizing from ethyl acetate.

EXAMPLE 293,4-Diphenyl-N-[3-(1-piperidinyl)propyl]-1H-pyrazole-1-acetamide(E)-2-butenedioate (1:1)

By a procedure substantially similar to that of Example 26, 8.56 g of3,4-diphenyl-N-[3-(1-piperidinyl)propyl]-1H-pyrazole-1-acetamide(E)-2-butanedioate (1:1), mp 179°-180° C., was prepared from 20 g (0.065mol) of ethyl 3,4-diphenyl-1H-pyrazole-1-acetate, 13.7 g (0.096 mol) of3-aminopropylpiperidine, and 78 mL (0.45 mol) of diisopropylethylamine.

EXAMPLE 30N-[2-(Diethylamino)ethyl]-3,4-diphenyl-1H-pyrazole-1-acetamide

A mixture of 10 g (0.033 mol) of ethyl3,4-diphenyl-1H-pyrazole-1-acetate, 6.9 mL (0.049 mol) ofdiethylaminoethylamine and 39 mL of diisopropylethylamine was stirred ona steam bath under nitrogen for 18 hours. The reaction was stripped, theresidue taken up in about 300 mL of ether and washed twice with water.The ether layer was extracted twice with a total of 150 mL of cold watercontaining 20 mL of 10% HCl. The combined water extracts were washedonce with ether, cooled, made basic with solid sodium carbonate,extracted several times with methylene dichloride, dried over sodiumsulphate, treated with decolorizing carbon, filtered and stripped. Theoily red residue was crystallized from ether to yield 6.86 g ofN-[2-(diethylamino)ethyl]-3,4-diphenyl-1H-pyrazole-1-acetamide, mp80°-83° C.

EXAMPLE 31 N-(3-Aminopropyl)-4,5-diphenyl-1H-pyrazole-1-acetamide(1:4)hydrate

A mixture of 7.96 g (0.026 mol) of ethyl3,4-diphenyl-1H-pyrazole-1-acetate and 19.2 g (0.26 mol) of1,3-diaminopropane in 13 mL of ethanol was stirred at 84°-87° C. for 3hours and the solvent removed in vacuo. The resulting solid waschromatographed on 34 g of silica gel eluting with 1% isopropylamine inchloroform and a gradient from 0-30% methanol. The impurities came offat 2-4% methanol followed by 6.95 g of pure product. It was crystallizedthree times from isopropyl acetate to yield 6 09 g ofN-(3-aminopropyl)-4,5-diphenyl-1H-pyrazole-1-acetamide (1:4) hydrate, mp119°-120° C.

EXAMPLE 32 N-(3-Hydroxypropyl)-4,5-diphenyl-1H-pyrazole-1-acetamide

A mixture of 1.47 g (48 mmol) of ethyl4,5-diphenyl-1H-pyrazole-1-acetate of Example 1, 0.72 g (9.6 mmol) of3-amino-1-propanol and 0.024 g (0.24 mmol) of triethylamine was stirredat 100° C. for two hours. Five mL of ethanol was added and the solutionwas poured into 20 mL of water and allowed to stand 18 hours at 5° C. tocrystallize. The product was filtered off, air-dried and recrystallizedfrom 25 mL of ethyl acetate to yield 1.47 g ofN-(3-hydroxypropyl)-4,5-diphenyl-1H-pyrazole-1-acetamide, mp 138°-139°C.

EXAMPLE 33 4,5-Diphenyl-N-[3-(ethylamino)propyl]-1H-pyrazole-1-acetamidehydrochloride

A. A solution of 10 g (0.03 mol) of 4,5-diphenylN-(3-hydroxypropyl)-1H-pyrazole-1-acetamide of Example 32 in 50 mL ofpyridine was stirred at 0°-5° C. and 5.2 mL (0.066 mol) ofmethanesulfonyl chloride was added dropwise over 30 minutes. Thereaction was filtered free of pyridine hydrochloride and added dropwiserapidly to 40 mL of ethylamine in 50 mL of pyridine at 0°-5° C. Thereaction was heated 30 minutes on a steam bath, stripped in vacuo,dissolved in 100 mL of water, washed once with ethyl acetate, madestrongly basic with aqueous KOH, extracted into ethyl acetate, dried andstripped to 9.9 g of free base which was a yellow oil. The oil wastreated with 75 mL of 5N HCl in ethanol and 5 g of product was filteredoff. The mother liquor was treated with about 75 mL of ether and asecond crop of product obtained. The total yield of4,5-diphenyl-N-[3-(ethylamino)propyl]-1H-pyrazole-1-acetamidehydrochloride was 6.5 g, m.p. 125°-137° C.

B. The dihydrochloride salt was prepared by dissolving 12 parts of thefree base in 12 parts of ethanol, adding 2 equivalents (about 12 partsby volume) of 5NHCl in ethanol, 1 part of water and 5 parts of ether.The resulting solid was filtered and recrystallized from isopropylalcohol to yield 58% of the dihydrochloride salt, mp 166°-174° C.

C. The fumarate salt was prepared by dissolving one part of the freebase in 6 parts of isopropyl alcohol, adding one equivalent of fumaricacid, heating to complete solution, cooling and filtering off thefumarate monohydrate, mp 127°-129° C. in 86% yield.

EXAMPLE 34N-[3-(Diethylamino)propyl]-4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-acetamide

A solution of 7.5 g (0.022 mol) of ethyl4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-acetate of example 4 in 35 mLof diethylaminopropylamine was stirred on a steam bath under nitrogenfor 14 hours. The diethylaminopropylamine was removed in vacuo and theresidue taken up in 200 mL of ethyl acetate. The ethyl acetate solutionwas washed twice with water, once with brine, and dried over sodiumsulfate. The solvent was removed in vacuo and the residue was distilledin a Kugelrohr at 250° C./0.1 mm to yield 6.39 g ofN-[3-(diethylamino)propyl]-4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-acetamideas a clear viscous amber oil.

EXAMPLE 35N-[3-(Diethylamino)propyl]-4-(4-hydroxyphenyl)-5-phenyl-1H-pyrazole-1-acetamide

A solution of 14 g (00.33 mol) ofN-[3-(diethylamino)propyl]-4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-acetamideof example 34 and 0.16 mol of the sodium salt of 1 propanethiol in 375mL of DMF was heated at 155°-160° C. for 2 hours. The reaction waschilled and the excess thiopropoxide was neutralized with ethanolic HCl.The DMF solution was stripped under vacuum at 30°, dissolved inmethylene dichloride, and washed with aqueous sodium carbonate, thenwater, and finally brine. The methylene chloride was dried over sodiumsulfate and the solvent removed in vacuo to yield 13.4 g of gummyproduct. Seven grams of the gummy product was chromatographed on asilica gel column eluted with methanol/isopropylamine/chloroform(2:3:95) to yield 5.1 g of purified product. The residue was taken up inisopropyl acetate, washed twice with water, washed once with brine, anddried over sodium sulfate. The isopropyl acetate was evaporated invacuo, but removal of the last traces of isopropyl acetate requiredextensive drying under high vacuum to yield 2.5 g of product as a glass.

EXAMPLE 36N-[3-(Diethylamino)propyl]-5-(4-hydroxyphenyl)-4-phenyl-1H-pyrazole-1-acetamide

A solution of 10 g (0.031 mol) of ethyl5-(4-hydroxyphenyl)-4-phenyl-1H-pyrazole-1-acetate of example 5 in 48 mLof diethylaminopropylamine was stirred on a steam bath under nitrogenfor 14 hours. The excess amine was removed in vacuo at 80° C., theresidue dissolved in ethyl acetate, washed twice with water, once withbrine and dried over sodium sulfate. They ethyl acetate was stripped toyield 12 g of a dark oil which was triturated in hot cyclohexane severaltimes. The insoluble residue was combined with a small amount of amixture of oil and crystals, which had separated from the cyclohexane oncooling, and recrystallized from ethyl acetate to yield 6.6 g ofproduct, mp 110°-113° C.

EXAMPLE 374,5-Diphenyl-N-[3-(2-methyl-1-piperidinyl)propyl]-1H-pyrazole-1-acetamidehemihydrate

A solution of 15 g (0.049 mol) of ethyl4,5-diphenyl-1H-pyrazole-1-acetate of example 1 in 17 mL (0.098 mol) of1-(3-aminopropyl)-2-pipecoline was stirred on a steam bath for fivehours. The solution was distributed between ether and water, the layersseparated, and the ether layer washed several times with water. Theether solution was dried over magnesium sulfate and stripped to about 20g of yellow oil. The oil was triturated in cyclohexane with a seedcrystal obtained from the aqueous layer upon standing. The resultingwhite solid was filtered off and rinsed with cyclohexane to yield 17.0 gof the hemihydrate, mp 75°-76° C.

EXAMPLE 38N-[2-[(1,1-dimethylethyl)amino]ethyl]-4,5-diphenyl-1H-pyrazole-1-acetamide

A solution of 10.7 g (0.035 mol) of ethyl 4,5-diphenylpyrazole-1-acetateof example 1 in 10.9 g (0.094 mol) of2-[(1,1-dimethylethyl)amino]ethanamine was heated with about 50 mg ofsodium methoxide at about 150° for two hours. The excess amine wasstripped off under vacuum and the residue was triturated inacetonitrile. The solid product was filtered off and recrystallized fromisopropyl acetate to yield 8.8 g of white crystals, mp 115°-116° C.

EXAMPLE 39N-[3-[(1,1-dimethylethyl)amino]propyl]-4,5-diphenyl-1H-pyrazole-1-acetamide(E)-2-butenedioate (1:1)

A solution of 9.18 g (0.03 mol) of ethyl 4,5-diphenylpyrazole-1-acetateof example 1 in 13.8 g (0.106 mol) of3-[(1,1-dimethylethyl)amino]propanamine was heated to about 100° C., thelower boiling material was allowed to boil off, and the temperature wasraised to 180° C. for one hour. The solution was cooled to 95° and theexcess amine was removed by vacuum distillation. The residual oil wasdissolved in 100 mL of acetone and treated with 3.48 g of fumaric acid.The acetone was stripped, the residue dissolved in methanol, andisopropyl alcohol was added. The solution was boiled down until theproduct crystallized. It was recrystallized from ethanol/acetonitrile toyield 4.88 g, mp 234°-235° C.

EXAMPLE 40N-[3-(Diethylamino)propyl]-4-(4-fluorophenyl)-5-phenyl-1H-pyrazole-1-acetamide

A solution of 8.73 g (0.027 mol) of ethyl4-(4-fluorophenyl)-5-phenyl-1H-pyrazole-1-acetate of example 6 in 30 mLof 3-(diethyl-amino)propanamine was heated at reflux for 3 hr. Theexcess amine was stripped under vacuum and the residue triturated in 1:1hexane/methyl t-butyl ether. The solid was recrystallized fromtriethylamine to yield 8.4 g of product, mp 82°-83° C.

EXAMPLE 414-(4-Chlorophenyl)-N-[3-(diethylamino)propyl]-5-phenyl-1H-pyrazole-1-acetamide

By a process analogous to that of example 40, 7.35 g of4-(4-chlorophenyl)-N-[3-(diethylamino)propyl]-5-phenyl-1H-pyrazole-1-acetamide,mp 104°-105° C. from triethylamine, was synthesized from 6.8 g (0.02mol) of ethyl 4-(4-chlorophenyl)-5-phenyl-1H-pyrazole-1-acetate ofexample 9 and 25 mL of 3-(diethylamino)propanamine.

EXAMPLE 424-(4-Bromophenyl)-N-[4-(ethylmethylamino)butyl]-5-phenyl-1H-pyrazole-1-acetamide

By a process substantially similar to that of Example 30 it iscontemplated that4-(4-bromophenyl)-N-[4-(ethylmethylamino)butyl]-5-phenyl-1H-pyrazole-1-acetamidemay be synthesized from N-ethyl-N-methyl-1,4-butanediamine and ethyl4-(4-bromophenyl)-5-phenyl-1H-pyrazole-1-acetate, which is synthesizedby a process substantially similar to that of Example 1A fromα-(bromophenyl)-β-oxobenzene-propanal.

EXAMPLE 434-(2-Chlorophenyl)-N-[3-[(1,1-dimethylethyl)amino]propyl]-5-(4-methoxyphenyl)-1H-pyrazole-1-acetamide

By a process substantially similar to that of Example 33 it iscontemplated that4-(2-chlorophenyl)-N-[3-[(1,1-dimethylethyl)amino]propyl]-5-(4-methoxyphenyl)-1H-pyrazole-1-acetamidemay be synthesized from tert-butylamine andN-[3-(methylsulfonyloxy)propyl]-4-(2-chlorophenyl)-5-(4-methoxyphenyl)-1H-pyrazole-1-acetamide.

EXAMPLE 44N-[7-(Diethylamino)heptyl]-4-(3-methylphenyl)-5-phenyl-1H-pyrazole-1-acetamide

By a process substantially similar to that of Example 30 it iscontemplated thatN-[7-(diethylamino)heptyl]-4-(3-methylphenyl)-5-phenyl-1H-pyrazole-1-acetamidemay be synthesized from N,N-diethyl-1,7-heptanediamine and ethyl4-(3-methylphenyl)-5-phenyl-1H-pyrazole-1-acetate, which is synthesizedby a process substantially similar to that of Example 1B from2-(3-methylphenyl)-1-phenylethanone.

EXAMPLE 45N-[3-(Diethylamino)propyl]-3,4-diphenyl-α-methyl-1H-pyrazole-1-acetamide

A mixture of 27.3 g (0.085 mol) of ethyl3,4-diphenyl-α-methyl-1H-pyrazole-1-acetamide of example 9 and 120 mL of3-(diethylamino)propanamine was heated 5 hr on a steambath. The reactionwas poured into water and extracted into ethyl acetate. The ethylacetate layer was dried and stripped to an oil in which a solid slowlycrystallized. The crystals were removed and recrystallized fromcyclohexane to yield 6.2 g ofN-[3-(diethylamino)propyl]-3,4-diphenyl-α-methyl-1H-pyrazole-1-acetamide,mp 87°-89° C.

EXAMPLE 46N-[3-(Diethylamino)propyl]-4,5-diphenyl-α-methyl-1H-pyrazole-1-acetamide

By a process substantially similar to that of example 45, it iscontemplated thatN-[3-(diethylamino)propyl]-4,5-diphenyl-α-methyl-1H-pyrazole-1-acetamidemay be synthesized from ethyl4,5-diphenyl-α-methyl-1H-pyrazole-1-acetate of example 8 and3-(diethylamino)propanamine.

EXAMPLE 47N-[3-[(1,1-Dimethylethyl)amino]propyl]-α-ethyl-4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-acetamide

By a process substantially similar to that of example 45, it iscontemplated thatN-[3-[(1,1-dimethylethyl)amino]propyl]-α-ethyl-4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-acetamidemay be synthesized from ethylα-ethyl-4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-acetate of example 11and 3-(t-butylamino)propylamine.

EXAMPLE 48N-[3-(Diethylamino)propyl]-α,α-dimethyl-4,5-diphenyl-1H-pyrazole-1-acetamide.

By a process substantially similar to that of example 45, it iscontemplated thatN-[3-(diethylamino)propyl]-α,α-dimethyl-4,5-diphenyl-1H-pyrazole-1-acetamidemay be synthesized from ethylα,α-dimethyl-4,5-diphenyl-1H-pyrazole-1-acetate of example 10 and3-(diethylamino)propanamine.

EXAMPLE 49N-[3-(Diethylamino)propyl]-4,5-diphenyl-1H-pyrazole-1-ethanamine(E)-2-butenedioate (1:2)

A solution of 11.5 g (0.029 mol) ofN-[3-(diethylamino)propyl]-4,5-diphenyl-1H-pyrazole-1-ethanamine ofexample 12 in 160 mL of THF was added dropwise with stirring at 0° C.under nitrogen to 240 mL of a 1M THF solution of diborane (0.024 mol).The reaction was slowly heated to reflux and allowed to reflux 18 hr.The solvent and excess diborane were stripped off in vacuo, and theresidue was treated with 400 mL of 6N HCl, cautiously at first, thenwith heating on steambath for 1 hr. The solution was cooled, made basicwith NaOH, and extracted into methylene chloride; the methylene chloridesolution was dried over MgSO₄ and stripped to a dark oil. The oil wasdissolved in hot ethanol and a solution of 2 equivalents of fumaric acidin hot ethanol was added. The solution was chilled and 8.7 g ofN-[3-(diethylamino)propyl]-4,5-diphenyl-1H-pyrazole-1-ethanamine(E)-2-butenedioate (1:2), mp 95°-100° C., was obtained by filtration.

EXAMPLE 50N-[3[(1,1-Dimethylethyl)amino]propyl]-α-ethyl-4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-ethanamine

By a process substantially similar to that of example 49, it iscontemplated thatN-[3-[(1,1-dimethylethyl)amino)propyl]-α-ethyl-4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-ethanaminemay be synthesized fromN-[3-[(1,1-dimethylethyl)amino]propyl]-α-ethyl-4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-acetamideof example 47.

EXAMPLE 51N-[3-(Diethylamino)propyl]-5-(4-hydroxyphenyl)-4-phenyl-1H-pyrazole-1-ethanamine.

By a process substantially similar to that of example 49, it iscontemplated thatN-[3-(diethylamino)propyl]-5-(4-hydroxyphenyl)-4-phenyl-1H-pyrazole-1-ethanaminemay be synthesized fromN-[3-(diethylamino)propyl]-5-(4-hydroxyphenyl)-4-phenyl-1H-pyrazole-1-acetamideof example 36.

EXAMPLE 52N-[3-(Diethylamino)propyl]-4,5-bis(4-fluorophenyl)-1H-pyrazole-1-ethanamine

By a process substantially similar to that of example 49, it iscontemplated thatN-[3-(diethylamino)propyl]-4,5-bis(4-fluorophenyl)-1H-pyrazole-1-ethanaminemay be synthesized fromN-[3-(diethylamino)propyl]-4,5-bis(4-fluorophenyl)-1H-pyrazole-1-acetamideof example 22.

The compounds of examples 1 to 44 are starting materials from whichcompounds of the invention may be prepared utilizing the procedures ofexamples 45 and 49.

The antiarrhythmic activity of compounds of the invention wasdemonstrated by the following procedure.

Duncan Hartley guinea pigs (600-900 grams) of either sex wereanesthetized with urethane (1.4 g/kg, i.p.) and supplemented as needed.An intravenous route for drug administration was established usingmicrobore tubing inserted into the jugular vein. The induction ofarrhythmias by aconitine hydrochloride (34 g/kg) was evaluated incontrol guinea pigs given 1 cc saline as an intravenous bolus 10 minutesprior to aconitine challenge.

Compounds to be tested were administered intravenously 10 minutes priorto aconitine challenge at an initial dosage of 30 mg/kg. This dosage wasreduced in subsequent animals if severe cardiac rhythm disturbancespersisted beyond two minutes after injection in the first guinea pigtested. All drugs were tested at the maximally tolerated dose(identified by the lack of arrhythmias in the EKG prior to aconitinechallenge). Compounds were administered in saline as 1 cc bolusinjections (n=5-9).

Time intervals between aconitine injection and the appearance ofarrhythmias were determined. Specifically noted was the time until theonset of (i) the first premature ventricular contraction (PVC); (ii) thefirst sustained run of ventricular tachycardia consisting of 10 or moreventricular beats (VTACH); and (iii) the time until the appearance ofventricular fibrillation lasting longer than 15 seconds (VFIB). Theaverage time and standard error of the mean until the appearance ofthese arrhythmias were calculated for each treatment group and comparedto concurrent controls using a one-way analysis of variance. Activitywas defined as a statistically significant delay in the onset of PVC,VTACH and VFIB time course compared to control values.

The following table summarizes the results obtained from the testing ofrepresentative compounds of the invention.

    ______________________________________                                        Example   Minutes to                                                          No.       PVC          VTACH    VFIB                                          ______________________________________                                        Control   0.7-1.0      1.0-2.0  3.7-7.9                                       45        13.5*        22.7     47.9                                          49        20.7*        48.6     57.3                                          ______________________________________                                         *not statistically significant                                           

The compounds of the invention can be prepared for use by conventionalpharmaceutical procedures: that is, by dissolving or suspending them ortheir pharmaceutically acceptable salts in a pharmaceutically acceptablevehicle, e.g., water, aqueous alcohol, glycol, oil solution or oil-wateremulsion, for parenteral or oral administration; or by incorporatingthem in unit dosage form as capsules or tablets for oral administrationeither alone or in combination with conventional adjuvants orexcipients, e.g., calcium carbonate, starch, lactose, talc, magnesiumstearate, gum acacia, and the like.

The percentage of active component in the composition and method fortreating or preventing arrhythmia can be varied so that a suitabledosage is obtained. The dosage administered to a particular patient isvariable depending upon the clinician's judgement using as the criteria:the route of administration, the duration of treatment, the size andcondition of the patient, the potency of the active component, and thepatient's response thereto. An effective dosage amount of activecomponent can thus be determined by the clinician considering allcriteria and utilizing his best judgement on the patient's behalf.

We claim:
 1. A compound of formula ##STR5## or acid addition saltthereof wherein R¹ is hydrogen or lower-alkyl; R² and R³ areindependently hydrogen, hydroxy, lower-alkyl, lower-alkoxy, or halo; R⁴and R⁵ are independently hydrogen or lower-alkyl, or R⁴ and R⁵ togetherform a straight or branched alkylene chain of four to six carbon atoms;R⁶ and R⁷ are independently hydrogen or straight-chain lower-alkylprovided that R⁶ and R⁷ are not both hydrogen; r is one; q is zero; andA is CH₂ CH(OH)CH₂ or (CH₂)_(n) wherein n is an integer from two toeight.
 2. A compound according to claim 1 wherein R¹ is hydrogen.
 3. Acompound according to claim 2 wherein n is two or three.
 4. A compoundaccording to claim 3 wherein r is one and q is zero and having theformula ##STR6##
 5. A compound according to claim 4 wherein one or bothof R⁶ and R⁷ are methyl. 6.N-[3-(Diethylamino)propyl]-α-methyl-3,4-diphenyl-1H-pyrazole-1-acetamideaccording to claim
 5. 7.N-[3-(Diethylamino)propyl]-α-methyl-4,5-diphenyl-1H-pyrazole-1-acetamideor acid addition salt or solvate thereof according to claim
 5. 8. Acomposition for treating cardiac arrhythmias comprising an amount of acompound according to claim 1 effective to treat cardiac arrhythmiastogether with one or more pharmaceutically acceptable excipients ordiluents.
 9. A composition for treating cardiac arrhythmias comprisingan amount of a compound according to claim 5 effective to treat cardiacarrhythmias together with one or more pharmaceutically acceptableexcipients or diluents.
 10. A composition for treating cardiacarrhythmias comprising an amount ofN-[3-(diethylamino)propyl]-α-methyl-4,5-diphenyl-1H-pyrazole-1-acetamideor pharmaceutically acceptable acid addition salt or solvate thereofaccording to claim 7 effective to treat cardiac arrhythmias togetherwith one or more pharmaceutically acceptable excipients or diluents. 11.A method for treating cardiac arrhythmias in a susceptible subject whichcomprises the step of administering an amount of a compound according toclaim 1 effective to treat cardiac arrhythmias.
 12. A method fortreating cardiac arrhythmias in a susceptible subject which comprisesthe step of administering an amount of a compound according to claim 5effective to treat cardiac arrhythmias.
 13. A method for treatingcardiac arrhythmias in a susceptible subject which comprises the step ofadministering an amount ofN-[3-(diethylamino)propyl]-α-methyl-4,5-diphenyl-1H-pyrazole-1-acetamideor pharmaceutically acceptable acid addition salt thereof according toclaim 7 effective to treat cardiac arrhythmias.